CCM (Cerebral Cavernous Malformations) is a common cerebrovascular disease characterized by the presence of vascular lesions in the CNS and retina, for which pharmacological therapies are currently lacking. The objective of this application is to test whether sustained inhibition of the mevalonate pathway by HMG-CoA reductase and prenylation inhibitors, respectively fluvastatin and zoledronic acid, represents a pharmacological therapy that can be applied to all genetic forms of familial CCM disease in pre-clinical models. Recent work in our laboratory identified these two medicines via a high-throughput screen of FDA-approved drugs and validated them in vitro and in vivo assays, demonstrating their efficacy in reversing outcomes of CCM3 loss in chronic and acute mouse models, reducing lesion burden, and extending survival. We now propose to test the generality of these findings across all genetic forms of CCM disease, by applying similar validation methodologies in the context of CCM1 and CCM2 protein loss. This work will establish fluvastatin and zoledronic acid for consideration as pharmacological options for familial, and possibly sporadic, CCM disease in patients.